JP6876017B2 - Olopatadine-containing aqueous composition - Google Patents

Description

The present invention relates to aqueous compositions.

Olopatadine has an antihistamine activity as well as an antiallergic action, and is used in an aqueous composition as a therapeutic agent for allergic or inflammatory disorders (Patent Document 1).

On the other hand, it is known that olopatadine is decomposed over time during storage by additives such as excipients, disintegrants, binders and lubricants, which are frequently used in the production of pharmaceutical preparations for oral administration. (Patent Document 2), a pharmaceutical product design in which oropatadine is stabilized is required (Patent Document 3).

Patent Document 4 reports a method for improving the stability of an olopatadine preparation by intentionally not containing crystalline cellulose in a solid preparation containing olopatadine.

Japanese Patent Publication No. 2004-536096 Japanese Patent No. 3828247 Japanese Unexamined Patent Publication No. 2011-105649 Japanese Unexamined Patent Publication No. 2011-20960

The present inventors have conducted various studies on an aqueous composition containing olopatazine, and found that the aqueous composition containing olopatazine and a nonionic surfactant is made of polyethylene terephthalate, polyethylene naphthalate, polypropylene, and the like. It has been found that the stability of olopatadine is significantly reduced when filled in any container selected from the group consisting of polyarylate, polybutylene terephthalate, polycarbonate and glass.

Therefore, an object of the present invention is to improve the stability of olopatadine in an aqueous composition contained in the above-mentioned container and containing olopatadine and a nonionic surfactant.

As a result of intensive studies, the present inventors have at least one selected from the group consisting of (A) olopatadine and a salt thereof (hereinafter, may be referred to as "(A) component"), (B) non-. At least one terpenoid selected from the group consisting of an ionic surfactant (hereinafter sometimes referred to as “component (B)”) and (C) menthol, camphor, borneol and cineole (hereinafter referred to as “(C)). The present invention has been found that even if the aqueous composition containing (sometimes referred to as “ingredient”) is contained in the above-mentioned container, the decrease in stability of the component (A) in the above-mentioned aqueous composition is suppressed. It came to be completed.

That is, the present invention provides the following [1] to [10].
[1] It is housed in any container selected from the group consisting of polyethylene terephthalate, polyethylene naphthalate, polypropylene, polyarylate, polybutylene terephthalate, polycarbonate and glass, and (A) olopatadine and its above. Contains at least one selected from the group consisting of salts, (B) a nonionic surfactant, and (C) at least one terpenoid selected from the group consisting of menthol, camphor, borneol and cineole. Aqueous composition.
[2] The aqueous composition according to [1], wherein the component (A) is olopatadine hydrochloride.
[3] The component (B) is selected from the group consisting of polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyethylene glycol monostearate and polyoxyethylene / polyoxypropylene block copolymer. The aqueous composition according to [1] or [2], which is at least one nonionic surfactant.
[4] The aqueous composition according to any one of [1] to [3], wherein the component (C) is menthol.
[5] The aqueous composition according to any one of [1] to [4], further containing (D) at least one selected from the group consisting of glycyrrhizic acid and a salt thereof.
[6] The aqueous composition according to [5], wherein the component (D) is dipotassium glycyrrhizinate.
[7] The aqueous composition according to any one of [1] to [6], which is a mucosal application composition.
[8] The aqueous composition according to [7], wherein the mucosal application composition is an ophthalmic composition.
[9] It is housed in any container selected from the group consisting of polyethylene terephthalate, polyethylene naphthalate, polypropylene, polyarylate, polybutylene terephthalate, polycarbonate and glass, and (A) olopatadine and its above. A method for stabilizing component (A) in an aqueous composition containing at least one selected from the group consisting of salts and (B) a nonionic surfactant, wherein the component (A), ( An aqueous composition containing component (A), component (B) and component (C) by mixing component B and at least one terpenoid selected from the group consisting of component (C) menthol, camphor, borneol and cineol. How to get things.
[10] At least one selected from the group consisting of (A) component, (B) component, (C) component and (D) glycyrrhizic acid and a salt thereof is mixed to form (A) component and (B) component. , The method according to [9], wherein an aqueous composition containing the component (C) and the component (D) is obtained.

The olopatadine-containing aqueous composition of the present invention contains a nonionic surfactant and consists of a group consisting of polyethylene terephthalate, polyethylene naphthalate, polypropylene, polyarylate, polybutylene terephthalate, polycarbonate and glass. The stability of olopatadine is improved by further containing at least one terpenoid selected from the group consisting of menthol, camphor, borneol and cineole while being contained in any of the selected containers. Therefore, the medicinal effect of olopatadine can be exhibited even when the aqueous composition is stored for a long period of time or exposed to a high temperature environment.

Further, the stability of olopatadine is further improved by further containing at least one selected from the group consisting of glycyrrhizic acid and a salt thereof in the olopatadine-containing aqueous composition of the present invention.

In the present specification, the unit of concentration "%" means "w / v%" and is synonymous with "g / 100 mL".

In the present specification, unless otherwise specified, the abbreviation "POE" means polyoxyethylene. In the present specification, unless otherwise specified, the abbreviation "POP" means polyoxypropylene.

The aqueous composition according to the present embodiment comprises at least one selected from the group consisting of (A) polycarbonate and salts thereof, (B) a nonionic surfactant, and (C) menthol, camphor, borneol and cineole. Contains at least one terpenoid selected from the group and is selected from the group consisting of polyethylene terephthalate, polyethylene naphthalate, polypropylene, polyarylate, polybutylene terephthalate, polycarbonate and glass. It is housed in a container.

Component (A) Olopatadine is a known compound having a chemical name of (Z) -11- (3-dimethylaminopropanol) -6,11-dihydrodibenzo [b, e] -oxepin-2-acetic acid, and is known. It may be synthesized by the method of the above, and it can also be obtained as a commercially available product.

The salt of olopatadine is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such salts include salts with inorganic acids [for example, hydrochlorides, bromine salts, sulfates, phosphates, sodium-orthophosphates, potassium hydrogen sulfates, etc.] and salts with organic acids. [For example, acetate, glycolate, lactate, pyruvate, malonate, succinate, glutarate, fumarate, malate, tartrate, citrate, ascorbate, maleic acid. Salts, hydroxymaleates, benzoates, hydroxybenzoates, phenylacetates, cinnamon salts, salicylates, 2-phenoxybenzoates, etc.].

These olopatadines and / or salts thereof may be used alone or in any combination of two or more. From the viewpoint of the effect of improving the stability of olopatadine in the aqueous composition, as the component (A), olopatadine or a salt thereof with an inorganic acid is preferable, and olopatadine hydrochloride is more preferable.

The concentration of the component (A) in the aqueous composition according to the present embodiment is not particularly limited, and the type of the component (A), the types and concentrations of the components (B) and (C) to be used in combination, the use of the aqueous composition, and the like. It is appropriately set according to the formulation form, usage method, and the like. Regarding the concentration of the component (A), for example, the total concentration of the component (A) is preferably 0.002 to 1 w / v% based on the total amount of the aqueous composition according to the present embodiment. It is more preferably 005 to 0.5 w / v%, further preferably 0.01 to 0.22 w / v%, and particularly preferably 0.01 to 0.11 w / v%. The concentration of the component (A) is suitable from the viewpoint of the effect of improving the stability of olopatadine in the aqueous composition.

(B) Ingredient The nonionic surfactant is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such nonionic surfactants include monolaurate POE (20) sorbitan (polysorbate 20), monooleic acid POE (20) sorbitan (polysorbate 80), and POE sorbitan monostearate (polysorbate 60). ), POE sorbitan fatty acid ester such as POE sorbitan tristearate (polysorbate 65); POE-cured castor oil 5, POE-cured castor oil 10, POE-cured castor oil 20, POE-cured castor oil 40, POE-cured castor oil 50, POE-cured POE-hardened castor oil such as castor oil 60 and POE-hardened castor oil 100; POE castor oil such as POE castor oil 3, POE castor oil 10, and POE castor oil 35; polyethylene glycol monostearate such as polyoxyl 40 stearate; POE ( 196) Polyoxyethylene / polyoxypropylene block copolymers such as POP (67) glycols (Poroxummer 407, Pluronic F127), POE (200) POP (70) glycols; (9) POE alkyl ether such as lauryl ether; POE / POP alkyl ether such as POE (20) POP (4) cetyl ether; POE alkylphenyl ether such as POE (10) nonylphenyl ether and the like. The numbers in parentheses indicate the number of additional moles.

These nonionic surfactants may be used alone or in combination of two or more.

In the aqueous composition according to the present embodiment, POE sorbitan fatty acid ester, POE cured castor oil, POE castor oil, polyethylene glycol monostearate and polyoxyethylene / polyoxypropylene block copolymer are preferable as the component (B), and POE sorbitan. Fatty acid esters, POE hardened castor oil, POE castor oil and polyethylene glycol monostearate are more preferred, with polysolvate 80, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil 10, and polyoxyethylene. The castor oil 35 and polyoxyl 40 stearate are more preferable, and polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene glycol oil 35 and polyoxyl 40 stearate are particularly preferable.

The concentration of the component (B) in the aqueous composition according to the present embodiment is not particularly limited, and the type of the component (B), the types and concentrations of the components (A) and (C) to be used in combination, the use of the aqueous composition, and the like. It is appropriately set according to the formulation form, usage method, and the like. As for the concentration of the component (B), for example, the total concentration of the component (B) is preferably 0.001 to 5.0 w / v% based on the total amount of the aqueous composition according to the present embodiment. It is more preferably 0.005 to 3.0 w / v%, further preferably 0.01 to 2.0 w / v%, and particularly preferably 0.05 to 1.5 w / v%. ..

Further, the content ratio of the component (B) to the component (A) in the aqueous composition according to the present embodiment is not particularly limited, and the types of the component (A) and the component (B), the use of the aqueous composition, and the formulation form. , It is set appropriately according to the usage method. The content ratio of the component (B) to the component (A) is, for example, the total content of the component (B) with respect to 1 part by mass of the total content of the component (A) contained in the aqueous composition according to the present embodiment. The amount is preferably 0.01 to 500 parts by mass, more preferably 0.05 to 200 parts by mass, further preferably 0.1 to 70 parts by mass, and 0.45 to 30 parts by mass. It is particularly preferable that it is a part. The content ratio of the component (B) to the component (A) is preferable from the viewpoint of further improving the stability of olopatadine in the aqueous composition.

Component (C) The terpenoid of the component (C) may be d-form, l-form or dl-form. However, cineole does not have optical isomers. Further, in the aqueous composition according to the present embodiment, the essential oil or plant extract containing the above terpenoid may be used. Examples of such essential oils include eucalyptus oil, peppermint oil, mentha oil and the like. In addition, Cool Mintha No. 71212 or the like may be used.

These terpenoids may be used alone or in any combination of two or more. From the viewpoint of improving the stability of olopatadine, l-menthol, d-camphor, dl-camphor, d-borneol and cineole are preferable, l-menthol, d-camphor, dl-camphor and cineole are more preferable, and l- Menthol is even more preferred.

The concentration of the component (C) in the aqueous composition according to the present embodiment is not particularly limited, and the type of the component (C), the types and concentrations of the components (A) and (B) to be used in combination, the use of the aqueous composition, and the like. It is appropriately set according to the formulation form, usage method, and the like. As the concentration of the component (C), for example, the total concentration of the component (C) is preferably 0.00001 to 1.0 w / v% based on the total amount of the aqueous composition according to the present embodiment, and is 0. It is more preferably 0005 to 0.5 w / v%, further preferably 0.001 to 0.1 w / v%, and particularly preferably 0.004 to 0.1 w / v%. When an essential oil containing the component (C) is used, the component (C) in the essential oil contained in the aqueous composition can be set to satisfy the above concentration. The concentration of the component (C) is preferable from the viewpoint of improving the stability of olopatadine.

Further, the content ratio of the component (C) to the component (A) in the aqueous composition according to the present embodiment is not particularly limited, and the types of the component (A) and the component (C), the use of the aqueous composition, and the formulation form. , It is set appropriately according to the usage method. The content ratio of the component (C) to the component (A) is, for example, the total content of the component (C) with respect to 1 part by mass of the total content of the component (A) contained in the aqueous composition according to the present embodiment. The amount is preferably 0.0005 to 100 parts by weight, more preferably 0.001 to 50 parts by mass, further preferably 0.005 to 20 parts by mass, and 0.04 to 10 parts by mass. It is particularly preferable that it is a part. The content ratio of the component (C) to the component (A) is preferable from the viewpoint of further improving the stability of olopatadine in the aqueous composition.

The aqueous composition according to the present embodiment is made of polyethylene terephthalate (PET), polyethylene naphthalate (PEN), polypropylene (PP), polyarylate (PAR), polybutylene terephthalate (PBT), polycarbonate (PC). It is housed in any container selected from the group consisting of made and made of glass. It is preferably made of PET, PEN, PP, PAR, PC and glass, and more preferably PET, PP and glass.

In the present specification, the container mainly means a container (primary container) for directly containing an olopatadine-containing aqueous composition. In addition, the container may have a lid or an extraction port attached to the main body of the container. The above material mainly means the material of the container body.

When the container containing the aqueous composition according to the present embodiment is made of a synthetic resin, the container may be molded from only a single synthetic resin, or may be molded by combining a plurality of synthetic resins. Good. When a plurality of synthetic resins are combined, the synthetic resins (PET, PEN, PP, PAR, PBT and PC) may be combined, and are usually used for molding a synthetic resin container in addition to the synthetic resin. Synthetic resins may be combined. Examples of such synthetic resins include polyester resins (polyethylene terephthalate resin, polyethylene naphthalate resin, polybutylene terephthalate, etc.), olefin resins (polyethylene, polypropylene, etc.), polyarylate resins, polyphenylene ether resins, polycarbonate resins, polysulfone-based resins. Examples thereof include resins such as resins, polyamide resins, polyimide resins, hard vinyl chloride resins, styrene resins (polystyrene, acrylonitrile-styrene copolymers, etc.), and cellulose acetates. Further, when a plurality of synthetic resins are combined, the method is not limited, and a copolymer of these synthetic resins may be used, these synthetic resins may be simply mixed, or the copolymers may be mixed. Good. The copolymer may be any of an alternating copolymer, a random copolymer, a block copolymer and a graft copolymer.

When the container containing the aqueous composition according to the present embodiment is a synthetic resin container, the total weight of PET, PEN, PP, PAR, PBT and PC with respect to the total weight of the constituent materials of the container is not particularly limited, but is preferable. The total weight of PET, PEN, PP, PAR, PBT and PC is 50 w / w% or more, more preferably 65 w / w% or more, and particularly preferably 80 w / w /, based on the total weight of the constituent materials of the container. It is w or more%. In a more preferred embodiment, the weight of any one of PET, PEN, PP, PAR, PBT and PC is 50 w / w% or more, 65 w / w% or more, or more than the weight of the entire constituent material of the container. It is 80 w / w% or more.

The container containing the aqueous composition according to the present embodiment may be a container to which an ultraviolet blocking agent has been added or coated. For example, a container formed after adding an ultraviolet blocking agent to a resin, a container formed by processing a resin into a sheet and then coated with an ultraviolet blocking agent, and then molding, and further, an ultraviolet blocking after molding the resin into a final container shape. Examples thereof include containers coated with an agent. Further, the sheet-like resin to which the ultraviolet blocking agent is added or coated may be shrink-wrapped or labeled in the container after molding.

Examples of the ultraviolet blocking agent include zinc oxide, titanium oxide, triazole compounds, benzoate compounds, substituted acrylonitrile compounds, cyanoacrylate compounds, triazine compounds, oxalic acid anilide compounds, nickel complex compounds; methyl diisopropylsilicate. , Synoxate, mono-2-ethylhexanate glyceryl diparamethoxycinnamic acid, isopropyl diisopropyl cinnamic acid ester mixture of paramethoxycinnamic acid, 2-ethylhexyl paramethoxycinnamic acid, benzyl cinnamic acid and other cinnamic acids Ultraviolet absorbers; paraaminobenzoic acid, ethyl paraaminobenzoate, glyceryl paraaminobenzoate, amyl paradimethylaminobenzoate, 2-ethylhexyl paradimethylaminobenzoate, 4- [N, N-di (2-hydroxypropyl) amino ] Cinnamic acid ester-based UV absorbers such as ethyl benzoate; cinnamic acid-based UV absorbers such as ethylene glycol salicylate, octyl salicylate, dipropylene glycol salicylate, phenyl salicylate, homomentyl salicylate, methyl salicylate, guaiazulene, dimethoxybenzilidendioxoimidazolidine 2-Ethylhexyl propionate, 2,4,6-tris [4- (2-ethylhexyloxycarbonyl) anilino] 1,3,5-triazine, parahydroxyanisole, 2- (2-hydroxy-5-methylphenyl) benzo Triazole, 4-tert-butyl-4'-methoxydibenzoylmethane, phenylbenzimidazole sulfonic acid, 2- (4-diethylamino-2-hydroxybenzoyl) -hexyl benzoate, hindered amine, riboflavin, anthraquinone dye (1-amino) -4-Methylanthraquinone, 1,4-diaminoanthraquinone, anthraquinone-based yellow, etc.), phthalocyanine-based pigments (C.I. Compound Blue 15; CI 74160; blue 404), phthalocyanine green (C. I. Compound Green 7), etc.) and the like.

The UV blocking agent is preferably zinc oxide, titanium oxide, 2-ethylhexyl paramethoxycinnamate, mono-2-ethylhexanate glyceryl diparamethoxycinnamate, 2,4,6-tris [4- (2). -Ethylhexyloxycarbonyl) anilino] 1,3,5-triazine, phenylbenzimidazoline sulfonic acid, 2- (4-diethylamino-2-hydroxybenzoyl) -hexyl benzoate, 2-ethylhexyl dimethoxybenzylidene dioxoimidazolidine propionate Can be mentioned. Zinc oxide and titanium oxide may be further coated with silica, silicon, zinc silicate or the like.

The container containing the aqueous composition according to the present embodiment may be a transparent container in which the inside of the container can be visually recognized, or an opaque container in which the inside of the container is difficult to see. Here, the "transparent container" includes both a colorless transparent container and a colored transparent container.

The aqueous composition according to the present embodiment preferably further contains at least one selected from the group consisting of (D) glycyrrhizic acid and a salt thereof.

Component (D) Glycyrrhizic acid is also called 20β-carboxy-11-oxo-30-noroleana-12-ene-3β-yl-2-O-β-D-glucopyranuronosyl-α-D-glucopyranoside uronic acid. It is a known compound, which may be synthesized by a known method, or may be obtained as a commercially available product.

The salt of glycyrrhizic acid is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, but specifically, it is the same as the salt that can be taken by component (A). The form is exemplified. Among these salts, a salt with an inorganic base is preferable, an alkali metal salt and / or an ammonium salt is more preferable, a sodium salt, a potassium salt and / or an ammonium salt is more preferable, and a potassium salt is particularly preferable. These salts of glycyrrhizic acid may be used alone or in combination of two or more.

Among glycyrrhizic acid and salts thereof, glycyrrhizic acid, an alkali metal salt thereof and / or an ammonium salt thereof are preferable from the viewpoint of obtaining a higher stability improving effect, and disodium glycyrrhizinate, trisodium glycyrrhizinate, and di-glycyrrhizinate di Potassium, tripotassium glycyrrhizinate and / or monoammonium glycyrrhizinate are more preferred, and dipotassium glycyrrhizinate is particularly preferred.

The concentration of the component (D) in the aqueous composition according to the present embodiment is not particularly limited, and the type of the component (D), the types and concentrations of the components (A), (B) and (C) to be used in combination, and the aqueous composition. It is appropriately set according to the intended use, formulation form, usage method and the like. Regarding the concentration of the component (D), for example, the total concentration of the component (D) is preferably 0.001 to 2 w / v% based on the total amount of the aqueous composition according to the present embodiment. It is more preferably 005 to 1 w / v%, further preferably 0.01 to 0.5 w / v%, and particularly preferably 0.01 to 0.25 w / v%. The concentration of the component (D) is preferable from the viewpoint of improving the stability of olopatadine.

Further, the content ratio of the component (D) to the component (A) in the aqueous composition according to the present embodiment is not particularly limited, and the types of the components (A) and (D), the use of the aqueous composition, and the formulation form. , It is set appropriately according to the usage method. The content ratio of the component (D) to the component (A) is, for example, the total content of the component (D) with respect to 1 part by mass of the total content of the component (A) contained in the aqueous composition according to the present embodiment. The amount is preferably 0.005 to 100 parts by mass, more preferably 0.01 to 50 parts by mass, further preferably 0.05 to 25 parts by mass, and 0.5 to 25 parts by mass. It is particularly preferable that it is a part. The content ratio of the component (D) to the component (A) is preferable from the viewpoint of further improving the stability of olopatadine in the aqueous composition.

The aqueous composition according to this embodiment can further contain a buffer. Thereby, the pH of the aqueous composition can be adjusted. The buffer is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such buffers include borate buffer, phosphate buffer, carbonic acid buffer, citric acid buffer, acetate buffer, tris buffer, aspartic acid, aspartate, epsilon-aminocaproic acid and the like. Be done. These buffers may be used alone or in any combination of two or more. Examples of the boric acid buffer include borates, borates such as alkali metal boric acid salts and alkaline earth metal boric acid salts. Examples of the phosphoric acid buffer include phosphates, or phosphates such as alkali metal phosphates and alkaline earth metal phosphates. Examples of the carbonic acid buffer include carbonic acid, or carbonates such as alkali metal carbonates and alkaline earth metal carbonates. Examples of the citric acid buffer include citric acid, an alkali metal citrate salt, and an alkaline earth metal citrate salt. Further, as a borate buffer or a phosphate buffer, a borate or a hydrate of a phosphate may be used. As a more specific example, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, boar sand, etc.) as a borate buffer; phosphoric acid or a salt thereof as a phosphate buffer. Salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); Or a salt thereof (sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.); as a citrate buffer, citric acid or a salt thereof (sodium citrate, potassium citrate, citrus) Calcium acidate, sodium dihydrogen citrate, disodium citrate, etc.); acetic acid or a salt thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.) as an acetate buffer; aspartic acid or a salt thereof (sodium aspartate, sodium aspartate) (Magnetic aspartate, potassium aspartate, etc.) and the like can be exemplified. Among these buffers, boric acid buffer (for example, a combination of boric acid and boric acid sand) and phosphate buffer (for example, a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate) are preferable. Acid buffers are even more preferred.

When the aqueous composition according to the present embodiment contains a buffer, the concentration thereof is appropriately determined according to the type of the buffer, the type and concentration of other contained components, the use of the aqueous composition, the formulation form, the method of use, and the like. Set. As the concentration of the buffer, for example, the total concentration of the buffer is preferably 0.01 to 15 w / v%, preferably 0.05 to 10 w / v%, based on the total amount of the aqueous composition of the present invention. It is more preferably 0.1 to 7.5 w / v%, and particularly preferably 0.5 to 5 w / v%.

The aqueous composition according to this embodiment can further contain a thickener. Thereby, the viscosity of the aqueous composition according to the present embodiment can be adjusted. Examples of the thickener include polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone (K25, K30, K90, etc.), carboxyvinyl polymer, cellulose derivative [methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc. (2208, 2906, 2910, etc.), carboxymethyl cellulose, carboxyethyl cellulose, nitrocellulose or salts thereof], polyethylene glycol (Macrogol 300, Macrogol 400, Macrogol 1500, Macrogol 4000, Macrogol 6000, etc.), Chondroitin Examples thereof include sodium sulfate, sodium hyaluronate, gum arabic, tragant, dextran (40, 70, etc.), glucose, sorbitol, etc., preferably polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone (K25, K30, K90), Carboxyvinyl polymer, cellulose derivatives (methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (2208, 2906, 2910), carboxymethyl cellulose or salts thereof, etc.), polyethylene glycol (Macrogol 300, Macrogol 400, Macrogol 4000, etc.) Macrogol 6000 etc.), dextran (70), more preferably polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone (K25, K30, K90), carboxyvinyl polymer, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose (2208). , 2906, 2910), carboxymethyl cellulose or a salt thereof, polyethylene glycol (macrogol 300, macrogol 400, macrogol 4000, macrogol 6000), dextran (70). These thickeners may be used alone or in any combination of two or more.

When the aqueous composition according to the present embodiment contains a viscous agent, the concentration thereof depends on the type of the viscous agent, the type and concentration of other contained components, the use of the aqueous composition, the formulation form, the method of use, and the like. Is set as appropriate. As for the concentration of the viscous agent, for example, the total concentration of the viscous agent is preferably 0.0001 to 5 w / v%, preferably 0.0005 to 3 w / v, based on the total amount of the aqueous composition of the present invention. It is more preferably v%, further preferably 0.001 to 1 w / v%, and particularly preferably 0.01 to 0.2 w / v%.

In addition, the aqueous composition according to this embodiment can further contain an isotonic agent. The tonicity agent is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such isotonic agents include disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, and magnesium chloride. , Potassium acetate, sodium acetate, sodium hydrogen carbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, glycerin, propylene glycol, polyethylene glycol, glucose, mannitol, sorbitol and the like. Among these isotonic agents, glycerin, propylene glycol, glucose, sodium chloride, potassium chloride, calcium chloride, or magnesium chloride is preferable, sodium chloride or glycerin is more preferable, and sodium chloride is further preferable. These isotonic agents may be used alone or in any combination of two or more.

When the aqueous composition according to the present embodiment contains an isotonic agent, the concentration thereof is determined by the type of the tonicity agent, the type and concentration of other contained components, the use of the aqueous composition, the formulation form, the method of use, etc. It is set appropriately according to. As the concentration of the tonicity agent, for example, the total concentration of the tonicity agent is preferably 0.01 to 10 w / v% based on the total amount of the aqueous composition according to the present embodiment. It is more preferably 05 to 5 w / v%, and even more preferably 0.1 to 3 w / v%.

The pH of the aqueous composition according to the present embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable range. The pH of the aqueous composition is, for example, preferably 4.0 to 9.5, more preferably 5.0 to 9.0, and even more preferably 5.5 to 8.5. ..

Further, the osmotic pressure of the aqueous composition according to the present embodiment is not particularly limited as long as it is within the range acceptable to the living body. The osmotic pressure ratio of the aqueous composition is, for example, preferably 0.5 to 5.0, more preferably 0.6 to 3.0, and further preferably 0.7 to 2.0. It is preferably 0.9 to 1.55, and particularly preferably 0.9 to 1.55. The osmotic pressure can be adjusted by a method known in the art using an inorganic salt, a polyhydric alcohol, a sugar alcohol, a sugar or the like. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (osmotic pressure of 0.9 w / v% sodium chloride aqueous solution) based on the 16th revised Japanese Pharmacy, and the osmotic pressure is the osmotic pressure measurement method described in the Japanese Pharmacy. Measure with reference to (freezing point descent method). For the standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution), sodium chloride (standard reagent of the Japanese Pharmacopoeia) is dried at 500 to 650 ° C. for 40 to 50 minutes, and then in a desiccator (silica). It can be allowed to cool in 1 and 0.900 g thereof is accurately weighed and dissolved in purified water to prepare exactly 100 mL, or a commercially available standard solution for measuring osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) can be used. ..

The viscosity of the aqueous composition according to the present embodiment is not particularly limited as long as it is within the range acceptable to the living body. The viscosity at 25 ° C. measured with a rotary viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1 ° 34'xR24) is preferably, for example, 0.01 to 1000 mPa · s, and is preferably 0.05. It is more preferably ~ 100 mPa · s, and further preferably 0.1 to 10 mPa · s.

In addition, the aqueous composition according to the present embodiment may contain various pharmacologically active ingredients and physiologically active ingredients in combination in an appropriate amount as long as the effects of the present invention are not impaired. Such an ingredient is not particularly limited, and examples thereof include active ingredients in various pharmaceutical products described in the 2000 edition of the Over-the-counter Drug Manufacturing (Import) Approval Standard (supervised by the Pharmaceutical Affairs Review Study Group). Specifically, the following components can be mentioned as components used in ophthalmic drugs.
Antihistamines or antiallergic agents: for example, ketotifen fumarate, iproheptin, diphenhydramine hydrochloride, chlorpheniramine maleate, potassium pemirolast, sodium cromoglycate and the like.
Decongestant: tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, naphazoline hydrochloride, naphazoline nitrate, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, dl-methylephrine hydrochloride and the like.
Eye muscle regulators: For example, cholinesterase inhibitors having an active center similar to acetylcholine, specifically neostigmine methylsulfate, tropicamide, atropine heleniensulfate and the like.
Disinfectants: for example, acrinol, cetylpyridinium, benzalkonium chloride, benzethonium chloride, chlorhexidine, polyhexamethylene biguanide, alkyldiaminoethylglycine hydrochloride and the like.
Vitamins: Flavin adenine dinucleotide sodium, cyanocobalamin, retinyl acetate, retinol palmitate, pyridoxine hydrochloride, panthenol, calcium pantothenate, sodium pantothenate, tocopherol acetate, etc.
Amino acids: potassium aspartate, magnesium aspartate, magnesium-potassium aspartate (equal mixture), aminoethylsulfonic acid, etc.
Anti-inflammatory agents: For example, allantin, berberine chloride, berberine sulfate, zinc sulfate, zinc lactate, glycyrrhetinic acid, methyl salicylate, glycol salicylate, sodium azulene sulfonate, tranexamic acid, epsilon-aminocaproic acid, lysozyme, licorice, pranoprofen and the like.
Others: For example, sodium hyaluronate, sulfamethoxazole, sulfamethoxazole sodium, indomethacin, ibuprofen, ibuprofen piconol, bufexamac, butyl flufenamic acid, bendazac, piroxicam, ketoprofen, felbinac, purple root, sardine, and These salts etc.

In addition, for the aqueous composition according to the present embodiment, various additives are appropriately selected according to a conventional method according to the use and the formulation form as long as the effects of the invention are not impaired, and one kind or the same. The above may be used in combination to contain an appropriate amount. Examples of these additives include various additives described in the Encyclopedia of Pharmaceutical Additives 2007 (edited by the Japan Pharmaceutical Additives Association). The following additives can be mentioned as typical components.
Carrier: An aqueous carrier such as water or hydrous ethanol.
Sugars: For example, glucose, cyclodextrin, etc.
Sugar alcohols: For example, xylitol, sorbitol, mannitol and the like. These may be D-form, L-form or DL-form.
Preservatives, bactericides or antibacterial agents: for example, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalconium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxy Methyl benzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biganide compounds (specifically, polyhexamethylene biganide, etc.), Glokill (Rhodia products) First name) etc.
Stabilizers: tromethamole, sodium formaldehyde sulfoxylate (longalit), tocopherol, sodium metabisulfite, monoethanolamine, aluminum monostearate, glycerin monostearate, etc.
Fragrances: Menton, geraniol, citronellol, carboxylic, anator, eugenol, limonene, linalool, linaryl acetate, bergamot oil, spearmint oil, fennel oil, kehi oil, rose oil, brain oil, etc.

The aqueous composition according to the present embodiment contains the above-mentioned component (A), component (B) and component (C), and if necessary, component (D) and other contained components in a carrier so as to have a desired concentration. Prepared by adding. For example, in the case of an ophthalmic composition, it can be prepared by dissolving or suspending the above components in purified water, adjusting the pH and osmotic pressure to a predetermined value, and sterilizing by filtration sterilization or the like. Regarding the dissolution of the above component (C) and other highly hydrophobic components, the mixture is previously stirred together with a component having a dissolution assisting action such as a surfactant (including the component (B)), and then purified water is further dissolved. May be added to dissolve or suspend.

In the present embodiment, the aqueous composition means a composition in which the concentration of water is 85 w / v% or more with respect to the total amount of the aqueous composition. The concentration of water in the aqueous composition is preferably 90 w / v% or more, more preferably 92 w / v% or more, further preferably 94 w / v% or more, and 96 w / v% or more. It is particularly preferable to have. As the water used in the aqueous composition according to the present embodiment, pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable water may be used, and as such water, specifically. , Distilled water, normal water, purified water, sterilized purified water, water for injection, distilled water for injection and the like are exemplified. The dosage form of the aqueous composition in the present embodiment is not particularly limited, but liquid preparations, semi-solid preparations (ointments, etc.) and the like can be mentioned, and liquid preparations are preferable. These definitions are based on the 16th revised Japanese Pharmacopoeia.

Further, since the aqueous composition according to the present embodiment can exhibit a pharmacological action based on the component (A), and when the aqueous composition also contains the component (D), the pharmacological action can be exhibited. , Anti-inflammatory, anti-allergic, etc., among others, inflammatory diseases of the external eye and anterior segment (blepharitis, conjunctivitis, keratitis, scleritis, epimyelitis, anterior uveitis) It can be used as a drug or a non-pharmaceutical product for symptomatic treatment of inflammation (flame, postoperative inflammation) and treatment of allergic conjunctivitis and vernal keratoconjunctivitis.

The aqueous composition according to the present embodiment can be used as a preparation for pharmaceuticals, non-pharmaceutical products, etc., for example, mucosal application compositions (ophthalmic compositions, nasal compositions, etc.), oral compositions, ear drops, etc. It can be used in various applications such as a composition, a composition for subcutaneous administration, and a composition for external use on the skin.

The aqueous composition according to the present embodiment is useful as a mucosal application composition applied to the ocular mucosa such as the corneum and conjunctiva, the oral mucosa, the nasal mucosa, and the pharyngeal mucosa.

Specific examples of the mucosal application composition according to the present embodiment include eye drops (also referred to as eye drops or eye drops; the eye drops include eye drops that can be instilled while wearing contact lenses) and artificial tears. Liquids, eye drops (also referred to as eye drops or eye drops; the eye drops include eye drops that can be washed while wearing contact lenses), eye ointments and other ophthalmic compositions; contact lens compositions [contact Lens mounting solution, composition for contact lens care (contact lens disinfectant, preservative for contact lens, cleaning agent for contact lens, cleaning preservative for contact lens), etc.]; Composition for nasal cavity such as eye drops and nasal cleaning solution Oral compositions such as oropharyngeal agents and mouthwashes (gargles); can be used as eye drops and the like. In view of the pharmacological actions of the components (A) and (D), the aqueous composition according to the present embodiment is preferably an ophthalmic composition, and more preferably an eye drop.

The above composition for contact lenses can be applied to all contact lenses including hard contact lenses and soft contact lenses. Further, the soft contact lens includes both ionic and nonionic, and is a silicone hydrogel contact lens (hereinafter, may be abbreviated as SHCL) and a non-silicone hydrogel contact lens (in the silicone hydrogel lens). Includes both non-soft contact lenses).

From another point of view, the present embodiment is housed in any container selected from the group consisting of polyethylene terephthalate, polyethylene naphthalate, polypropylene, polyarylate, polybutylene terephthalate, polycarbonate and glass. , A method for stabilizing the component (A) in an aqueous composition containing the component (A) and the component (B), wherein the component (A), the component (B) and the component (C) are mixed. It provides a method for obtaining an aqueous composition containing the component (A), the component (B) and the component (C). The component (A), the component (B) and the component (C) may be mixed in any order, and the finally obtained aqueous composition has the component (A), the component (B) and the component (C). As long as the component (A) is stabilized. In the above method, the component (D) is preferably mixed to obtain an aqueous composition containing the component (A), the component (B), the component (C) and the component (D). The component (A), the component (B), the component (C) and the component (D) may be mixed in any order, and the finally obtained aqueous composition is the component (A), the component (B), (C). As long as it has the component () and the component (D), the component (A) is stabilized.
Further, from another point of view, the present embodiment contains the component (A), the component (B) and the component (C) in the aqueous composition, and the aqueous composition is made of polyethylene terephthalate or polyethylene naphthalate. A method for producing an aqueous composition in which the component (A) is stabilized by containing it in a container selected from the group consisting of polypropylene, polyarylate, polybutylene terephthalate, polycarbonate and glass. It is to provide.

Hereinafter, the present invention will be described in detail with reference to Examples and Test Examples, but the present invention is not limited to these Examples and the like. When conducting the test using a plastic container, the weight of the sample was measured before and after storage to determine the transpiration rate, and the change in concentration due to transpiration was corrected.

[Test Example 1 Stability Test (1)]
An aqueous composition was prepared according to Table 1 below, and the stability of olopatadine or a salt thereof was evaluated.

First, each aqueous composition shown in Table 1 was prepared by a conventional method. Next, 5 mL of the prepared aqueous composition was placed in a polyethylene terephthalate container (PET; capacity 15 mL), a polypropylene container (PP; capacity 15 mL), a polyethylene container (PE; capacity 10 mL), and a polystyrene container (PS; capacity 15 mL). It was filled and sealed one by one, and stored in a constant temperature machine at 50 ° C. under shading. 14 days after the start of storage, each test solution was taken out, the content of olopatadine hydrochloride in the aqueous composition was quantified by using high performance liquid chromatography (HPLC), and the residual rate of olopatadine hydrochloride was calculated according to the following formula (I). did.
Equation (I)
Residual rate (%) = (Olopatadine hydrochloride content after storage) / (Olopatadine hydrochloride content before storage) x 100

As shown in Table 1, when the aqueous composition containing olopatadine hydrochloride is stored in a container made of polyethylene terephthalate, if the aqueous composition contains polysorbate 80, which is a nonionic surfactant, olopatadine hydrochloride remains. It was found that the rate decreased and the stability of olopatadine hydrochloride decreased (Reference Example 1-1 and Comparative Example 1-1). However, when the aqueous composition further contained l-menthol, which is a terpenoid, the residual rate of olopatadine hydrochloride increased, and the stability of olopatadine hydrochloride was improved (Example 1-1). The same phenomenon was observed even when the aqueous composition containing olopatadine hydrochloride was stored in a polypropylene container (Reference Example 1-2, Comparative Example 1-2 and Example 1-2).

On the other hand, when the aqueous composition containing olopatadine hydrochloride is stored in a polyethylene container, the residual rate of olopatadine hydrochloride hardly decreases even if the aqueous composition contains polysorbate 80, and olopatadine hydrochloride is stable. There was almost no decrease in sex (Reference Examples 1-3 to 1-5). A similar phenomenon was observed when the aqueous composition containing olopatadine hydrochloride was stored in a polystyrene container.

[Test Example 2 Stability Test (2)]
An aqueous composition was prepared according to Table 2 below, and the stability of olopatadine or a salt thereof was evaluated. The residual ratio of olopatadine hydrochloride was determined in the same manner as in Test Example 1 above, except that the aqueous composition was filled in a glass headspace vial (capacity: 10 mL).

As shown in Table 2, when the aqueous composition containing olopatadine hydrochloride is stored in a glass container, if the aqueous composition contains polysorbate 80, the residual rate of olopatadine hydrochloride decreases and the stability of olopatadine hydrochloride It was found that the sex was reduced (Reference Example 2 and Comparative Example 2). Further, when the aqueous composition further contained l-menthol, the residual rate of olopatadine hydrochloride increased, and the stability of olopatadine hydrochloride was improved (Example 2).

[Test Example 3 Stability Test (3)]
An aqueous composition was prepared according to Table 3 below, and the stability of olopatadine or a salt thereof was evaluated. The residual rate of olopatadine hydrochloride was determined in the same manner as in Test Example 1 above, except that the storage temperature was changed from 50 ° C. to 70 ° C. and the aqueous composition was filled in a glass headspace vial (capacity: 10 mL). It was. Storage at 70 ° C. for 14 days corresponds to storage at room temperature for about 3 years.

As shown in Table 3, even when the aqueous composition containing olopatadine hydrochloride is stored at 70 ° C., if the aqueous composition contains polysorbate 80, the residual rate of olopatadine hydrochloride decreases and the stability of olopatadine hydrochloride Was found to decrease (Reference Example 3 and Comparative Example 3-1). Further, when the aqueous composition further contained l-menthol, the residual rate of olopatadine hydrochloride increased, and the stability of olopatadine hydrochloride was improved (Example 3-1-1). When the aqueous composition contained dipotassium glycyrrhizinate in addition to l-menthol, the stability was further improved as compared with the case where the aqueous composition contained l-menthol (Example 3-1-2). ).
Similarly, when polyoxyl 40 stearate is contained as a nonionic surfactant, the residual rate of olopatadine hydrochloride decreases, and when l-menthol is further contained, the residual rate of olopatadine hydrochloride increases. And the stability was improved (Comparative Example 3-2, Example 3-2).

[Test Example 4 Stability Test (4)]
An aqueous composition was prepared according to Table 4 below, and the stability of olopatadine or a salt thereof was evaluated. Test Example 1 above, except that the storage temperature was changed from 50 ° C. to 60 ° C., the storage period was changed from 14 days to 7 days, and the aqueous composition was filled in a glass headspace vial (capacity: 10 mL). In the same manner as above, the residual rate of olopatadine hydrochloride was determined.

When the aqueous composition containing olopatadine hydrochloride contains the terpenoid d-borneol or cineole, it also contains a nonionic surfactant as in the case where it contains l-menthol. As a result, the reduced stability of olopatadine hydrochloride was improved (Comparative Example 4, Example 4-1 and Example 4-3). Further, when the aqueous composition contained d-borneol, which is a terpenoid, the stability of olopatadine hydrochloride was further improved when dipotassium glycyrrhizinate was further contained (Examples 4-1 and Examples). 4-2).

[Test Example 5 Stability Test (5)]
An aqueous composition was prepared according to Table 5 below, and the stability of olopatadine or a salt thereof was evaluated. The residual ratio of olopatadine hydrochloride was determined in the same manner as in Test Example 1 above, except that the storage temperature was changed from 50 ° C. to 70 ° C. and the aqueous composition was filled in a polyethylene terephthalate container (capacity: 15 mL).

As shown in Table 5, even when the aqueous composition containing olopatazine hydrochloride contains polyoxyethylene hydrogenated castor oil 60 and polyoxyethylene castor oil 35 as nonionic surfactants, Test Examples 1 to 4 Similarly, when terpenoid was contained, the stability of olopatadine hydrochloride, which was reduced due to the inclusion of the nonionic surfactant, was improved.

[Test Example 6 Stability Test (6)]
An aqueous composition was prepared according to Table 6 below, and the stability of olopatadine or a salt thereof was evaluated. The residual ratio of olopatadine hydrochloride was determined in the same manner as in Test Example 1 above, except that the aqueous composition was filled in a glass headspace vial (capacity: 10 mL).

As shown in Table 6, when the aqueous composition containing olopatadine hydrochloride contains the terpenoid d-borneol or cineole, as in the case of containing l-menthol, the nonionic surfactant is active. The stability of olopatadine hydrochloride, which was reduced by the inclusion of the agent, was improved (Comparative Example 6-1, Example 6-1 and Example 6-2).

[Test Example 7 Stability Test (7)]
An aqueous composition was prepared according to Table 7 below, and the stability of olopatadine or a salt thereof was evaluated. Similar to Test Example 1 above, except that the storage temperature was set to 60 ° C., the storage period was changed from 14 days to 30 days, and the aqueous composition was filled in a glass headspace vial (capacity: 10 mL). , The residual rate of olopatadine hydrochloride was determined.

As shown in Table 7, when the aqueous composition containing olopatadine hydrochloride contains the terpenoid d-borneol or cineole, as in the case of containing l-menthol, the nonionic surfactant is active. The stability of olopatadine hydrochloride, which was reduced by the inclusion of the agent, was improved (Comparative Example 7-1, Example 7-1, Example 7-2).

[Test Example 8 Stability Test (8)]
When the same test as in Test Examples 1 to 7 is performed and the stability of olopatadine hydrochloride is lowered and the terpenoid is further contained even in the aqueous composition in which the concentration of polysorbate 80 is 0.05 w / v%. It was confirmed that the stability was improved.

[Formulation example]
An aqueous composition was prepared according to Formulation Examples 1 to 13 in Tables 8 to 9 below, and the product (eye drops or eye wash) filled in a polyethylene terephthalate container was designated as Formulation Examples 1 to 13 and filled in a polypropylene container. (Eye drops or eye wash) were designated as Preparation Examples 14 to 26. The continuation of Table 8-1 is shown in Table 8-2, and the continuation of Table 9-1 is shown in Table 9-2.

Claims (11)

It is housed in any container selected from the group consisting of polyethylene terephthalate, polypropylene and glass.
(A) At least one selected from the group consisting of olopatadine and its salts, and
(B) Nonionic surfactant and
A method for stabilizing component (A) in an aqueous composition containing the above when exposed to a high temperature environment.
Aqueous composition containing (A) component, (B) component and (C) component by mixing (A) component, (B) component and (C) menthol (however, the total amount of propylene glycol in the aqueous composition) (Excluding aqueous compositions containing 0.5 w / v% based on
(A) The total concentration of the components, Ri 0.1~0.11w / v% der based on the total amount of the aqueous composition,
A method in which the total concentration of the component (C) is 0.004 to 0.1 w / v% based on the total amount of the aqueous composition . At least one selected from the group consisting of component (A), component (B), component (C) and (D) glycyrrhizic acid and a salt thereof is mixed to form component (A), component (B), and (C). The method according to claim 1, wherein an aqueous composition containing the component (D) and the component (D) is obtained. The method according to claim 2, wherein the total concentration of the component (D) is 0.001 to 2 w / v% based on the total amount of the aqueous composition. The method according to claim 2, wherein the total content of the component (D) is 0.005 to 100 parts by mass with respect to 1 part by mass of the total content of the component (A) contained in the aqueous composition. The method according to any one of claims 2 to 4, wherein the component (D) is dipotassium glycyrrhizinate. The method according to any one of claims 1 to 5 , wherein the total concentration of the component (B) is 0.001 to 5.0 w / v% based on the total amount of the aqueous composition. Any one of claims 1 to 5 , wherein the total content of the component (B) is 0.01 to 500 parts by mass with respect to 1 part by mass of the total content of the component (A) contained in the aqueous composition. The method described in the section. (B) At least one selected from the group consisting of polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyethylene glycol monostearate and polyoxyethylene polyoxypropylene block copolymer. The method according to any one of claims 1 to 7 , which is a nonionic surfactant of the above. The method according to any one of claims 1 to 8 , wherein the component (A) is olopatadine hydrochloride. The method according to any one of claims 1 to 9 , wherein the aqueous composition is a mucosal application composition. The method according to claim 10 , wherein the mucosal application composition is an ophthalmic composition.